Psychopharmacology (2011) 215:527–536 DOI 10.1007/s00213-011-2184-9
ORIGINAL INVESTIGATION
MDMA and methamphetamine: some paradoxical negative and positive mood changes in an acute dose laboratory study Andrew C. Parrott & Amy Gibbs & Andrew B. Scholey & Rebecca King & Katherine Owens & Phil Swann & Ed Ogden & Con Stough
Received: 25 June 2010 / Accepted: 17 January 2011 / Published online: 12 February 2011 # Springer-Verlag 2011
Abstract Rationale This study investigated the acute mood effects of oral MDMA, methamphetamine, and placebo in a double-blind laboratory study. Methods Fifty-two healthy participants comprised abstinent recreational users of stimulant drugs, 27 female and 25 male, mean age 24.8 years. Three test sessions involved acute 100 mg oral 3.4-methylendioxymethamphetamine (MDMA), 0.42 mg/kg oral methamphetamine, and matching placebo. Drug administration was counterbalanced, testing was double-blind, and medical supervision was present throughout. Car-driving performance on a laboratory simulator was assessed after 3 and 24 h, with the findings being presented elsewhere. Positive and negative moods (PANAS self-ratings) were completed before drug administration, 3, 4.5, and 24 h later. Blood samples were taken to monitor drug plasma levels. Results Following MDMA, there were no significant increases in positive moods, whereas negative moods were significantly higher than under placebo. Methamphetamine led to significant increases in both positive and negative moods. The MDMA findings contrast with the elated moods, typically noted by dance clubbers on Ecstasy. A. C. Parrott : A. Gibbs : A. B. Scholey : R. King : K. Owens : P. Swann : C. Stough Brain Sciences Institute, Swinburne University, Melbourne, VIC, Australia E. Ogden Vicroads, Victorian Government, Kew, Melbourne, VIC, Australia A. C. Parrott (*) Department of Psychology, Swansea University, Swansea SA2 8PP, UK e-mail:
[email protected]
However, they are consistent with some previous laboratory findings, since a wide array of positive and negative mood changes have been demonstrated. One possible explanatory factor was the neutral environmental situation, particularly if a primary action of MDMA is to intensify ongoing psychological states. Other explanatory factors, such as dosage, gender, post-drug timing, neurohormonal aspects, and social factors, are also discussed. Conclusions In the laboratory, acute methamphetamine led to significantly higher positive moods. However, against expectations, MDMA did not generate a significant increase in positive moods. Keywords MDMA . Ecstasy . Methamphetamine . Mood . Environment . PANAS . Serotonin . Dopamine
Introduction The ring-substituted methamphetamine derivative, MDMA (3,4-methylendioxymethamphtamine), is a powerful CNS stimulant, which increases activity across several neurotransmitter and neurohormonal systems (Cadet et al. 2007; Degenhardt and Hall 2009; Dumont and Verkes 2006; Green et al. 2003). In recreational users, this powerful neurobiological activation can be strongly euphoric. Solowij et al. (1992) noted that the main effect of Ecstasy was a positive mood state encompassing feelings of euphoria, intimacy, and closeness. In a questionnaire survey of 466 recreational users, Verheyden et al. (2003) reported that 91% reported experiencing a ‘euphoric rush’ following Ecstasy. These positive moods are illustrated by quotations from individual users: ‘I loved everything. Life was beautiful’, and ‘I felt utter bliss’ (Cohen 1998), ‘Imagine the best feeling you have ever felt, times it by ten and you’re still not close to
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how amazing you feel’ (Parrott 2010). In laboratory trials also, MDMA can induce strong feelings of happiness and elation. Liechti et al. (2001) summarized three placebocontrolled trials, where oral doses of MDMA (mean 108 mg) were administered to 74 drug-naive participants. Significant increases were found on every positive mood scale, including greater ‘emotional excitation’, and higher ‘positive mood’ (Liechti et al. 2001). Many other laboratory studies have similarly reported positive mood changes, following various dosage levels, and with different mood questionnaires (Cami et al. 2000; Bedi et al. 2009, 2010; Bedi and de Wit 2010; Dumont et al. 2009, 2010; Hernández-López et al. 2002; Kolbrich et al. 2008; Tancer and Johanson 2001, 2003, 2007). Though less widely reported, negative moods can also be boosted by MDMA. Several placebo-controlled laboratory studies have reported significant increases in negative types of feeling state. Liechti et al. (2001) found significant increases in ‘apprehensiveness–anxiety’, ‘depressiveness’, and other negative mood scales, following an acute dose of 108 mg MDMA. They also observed women to report more intense subjective experiences whilst on drug, especially relating to disordered thought, perceptual changes, and fear of loss of body control; acute adverse MDMA reactions were also noted more frequently by females. Tancer and Johanson (2007) reported a significant increase in anxiety after 2 mg/kg oral MDMA. Bedi and de Wit (2010) found significantly higher self-ratings of feeling anxious in females than males, following both low and high doses of oral MDMA. They further noted that: ‘Females also showed greater decreases in self-rated elation and positive mood after MDMA (0.75 mg/kg only) than males’. Negative mood experiences are not restricted to the laboratory. Ecstasy-using dance clubbers can also report negative moods, with occasional feelings of panic, overstimulation, or loss of personal control (Davison and Parrott 1997). Hence, the following quotation from a dance clubber: ‘I had a bad experience. I felt like I was surrounded by water and drowning. It must have been panic’ (Cohen 1998). Furthermore, positive and negative mood changes often occur in the same individual, with users feeling more sociable/extraverted and more reflective/ introverted during the same drug experience. Hence, the overall mood effects of MDMA can often appear paradoxical, with self-rated introversion and extraversion, happiness and depressiveness, all significantly heightened post-MDMA (Liechti et al. 2001). Another of Cohen’s recreational users reported ‘I did experience mood fluctuations—ups and downs’. One potential explanation for this mixture of effects is that MDMA is essentially a mood intensifier. Its primary effect is to enhance neurobiological activation across several neurotransmitter and neurohormonal systems (Green et al. 2003; Parrott 2001, 2009). Hence, many different internal
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psychobiological states can be intensified by MDMA, as illustrated by this quotation from a recreational user: ‘Ecstasy is not a happy drug. It by itself does not do anything. The Ecstasy and joy must come from within you’ (Cohen 1998). The present study was one of a series of laboratory studies funded by the Victoria State of Australia, into the effects of recreational drugs on car driving skills (Silber et al. 2006; Papafotiou et al. 2005). The two drugs assessed here were the ring-substituted methamphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA), and the parent compound methamphetamine (Green et al. 2003; Cadet et al. 2007). Both drugs are powerful CNS stimulants, and used recreationally by dance clubbers worldwide (Yacoubian et al. 2003; M ter Bogt and Engels 2005; Clemens et al. 2007). The common street name for MDMA is ‘Ecstasy’ (Solowij et al. 1992; Parrott 2004a), while methamphetamine is often called ‘Ice’ (Clemens et al. 2007). In this study, every participant had previously used illicit stimulant drugs for recreational purposes. They were assessed on a car driving simulator, to investigate the performance effects of these drugs in a controlled laboratory setting. Mood self-ratings were assessed for four reasons. Firstly, to provide more empirical data on the mood effects of acute MDMA. Secondly, to generate comparative mood data for MDMA against its parent compound methamphetamine. Thirdly, to investigate potential gender differences. Finally, to study mood changes in a laboratory setting, since previous studies have suggested an important contributory role for the environmental conditions (Parrott 2004b; Greer and Tolbert 1990).
Methods Participants The sample comprised 52 individuals from Melbourne, 27 female and 25 male, aged between 21 and 34 years (mean 24.8, SD 3.1). The first criterion for acceptance was previous consumption of any illegal stimulant drug from the amphetamine class for recreational purposes. Every volunteer underwent a formal medical examination by a medical practitioner, in order to ensure physical and mental health. Hence, each participant was free from any history of cardiac disorder, mental health problems, drug allergies, or other illnesses. Menstrual phase was not recorded. Each participant was provided with a written information sheet about the study. Any verbal questions were answered, and those who agreed signed the written consent form. They were informed that they were free to withdraw from the study at any time. The study was approved by the Swinburne University Human Research Ethics Committee. Participants received $500 (AUD) on completion of the three testing sessions.
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Lifetime drug usage Participants completed a Drug Use Questionnaire covering drugs ever consumed, frequency of consumption, and time since last usage. Past Ecstasy/ MDMA usage ranged from 0 to 300 pills; only two participants had not used it before, but they had used other drugs in the amphetamine class. The overall mean lifetime consumption was 55 Ecstasy tablets, which represents a good estimate for prior MDMA usage, given the high concordance between Ecstasy and MDMA (Parrott 2004a; Scholey et al. 2010). The frequency of drug use for the various drug types in summarized in Table 1. This demonstrates a pattern of moderate alcohol use, moderate cannabis use, and moderate stimulant drug usage. None of the participants was a heavy stimulant drug user, with no reports of weekly or more frequent usage, for MDMA, cocaine, or amphetamines (Table 1). Heroin and inhalant usage were minimal. Of the 52 participants, 32 were tobacco smokers (mean 8.29 cigarettes/day). They were allowed to smoke normally, since nicotine maintenance allows mood and cognition to remain within normal bounds, whereas nicotine deprivation leads to significant mood and cognitive decrements (Parrott 1994, 1999). Acute drug administration Drug administration was double-blind and placebo-controlled. MDMA (3, 4methylenedioxymethamphetamine) was administered as a 100-mg dose, in four 25 mg gelatin capsules (weightcorrected range 0.8–2.0 mg/kg). Methamphetamine was given as a weight-related dose of 0.42 mg/kg, in a combination of capsules containing 0, 2, 5, 10, or 20 mg methamphetamine (mean weight-corrected dosage: 30 mg). The weight-corrected methamphetamine dose was selected to duplicate the dosage level employed in our earlier driving simulator study (Silber et al. 2006). The emergent group mean dose of 30 mg was equivalent to the typical oral dose cited in the methamphetamine review by Cruickshank and Dyer (2009; their Table 1). The MDMA dose of 100 mg was chosen to represent a moderate dose, identical to that used in previous laboratory trials (Dumont
et al. 2009; Farré et al. 2004), although lower and higher doses have also been employed safely (Bedi et al. 2010; Cami et al. 2000; Tancer and Johanson 2003). We selected a standard oral dosage as many studies have followed this practice (Dumont et al. 2009; Farré et al. 2004), although weight-corrected doses have also often been employed (Tancer and Johanson 2003, 2007). It may be noted that the only other group to directly compare MDMA with methamphetamine, employed a standard oral dose for methamphetamine, but weight-corrected doses for MDMA (Bedi et al. 2009, 2010). Oral MDMA has a shorter half-life than oral methamphetamine, with peak effects between 1–4 h for MDMA (Tancer and Johanson 2003; Bedi et al. 2010), and 3–5 h for methamphetamine (Cruickshank and Dyer 2009). This helped to determine the timing for the post-drug sessions, at 3 and 4.5 h (see below). Turning to the placebo condition, the lactose capsules were visually indistinguishable from the active drug conditions. Each participant was administered the same number of capsules every session. The methamphetamine and MDMA were purchased from Lipomed, Arlesheim, Switzerland. Assessment measures As part of the initial screening, participants completed a Demographics Questionnaire, Medical History Questionnaire, and Physical Examination Questionnaire. These determined whether the participants met all the eligibility requirements. The Lifetime Drug Usage Questionnaire was completed prior to testing. Mood was assessed using the Positive Affect and Negative Affect Scale PANAS (Watson et al. 1988). This 20-item self-rating questionnaire provides separate indices for positive and negative affect, with ten mood adjectives covering each factor. Participants indicated how they were feeling at the moment, with five response choices ranging from ‘slightly’ (1) to ‘extremely’ (5). The other aim of the study was to assess the effects of MDMA and methamphetamine on car driving skills. The simulated driving task assessed basic steering accuracy, use of the pedals under different real life scenarios: day and night, in the city, and on the freeway
Table 1 Frequency of self-reported recreational drug use. Figures are total number of participants and percentage of whole sample (in brackets) Alcohol Daily 1–2 times week 2–3 times month Once a month Once every 2 months Few times a year Rarely/once Never
Cannabis
Amphetamines
7 (13.46) 36 (69.23) 7 (13.46)
3 (5.77) 7 (13.46) 5 (9.62)
0 0 2 (3.85)
2 (3.85) 0 0 0 0
6 (11.54) 0 15 (28.85) 16 (30.77) 0
10 (19.23) 2 (3.85) 17 (32.69) 20 (38.46) 1 (1.92)
MDMA 0 0 3 (5.77) 8 (15.38) 7 (13.46) 16 (30.77) 16 (30.77) 2 (3.85)
Cocaine
Heroin
Inhalants
0 0 0
0 0 0
0 0 0
4 1 (1.92) 5 (9.62) 27 (51.92) 15 (28.85)
0 1 (1.92) 0 7 (13.46) 44 (84.62)
0 0 0 5 (9.62) 47 (90.38)
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(Papafotiou et al. 2005). Further details of the car driving simulator, along with the emergent findings, are being presented elsewhere. Procedure Testing began at either 10 A.M. or 12 midday, and participants maintained the same testing schedule for each session, with a minimum of a 2-week washout period between drug conditions. Upon arrival at the Brain Sciences Institute (BSI) laboratory at Swinburne University, participants were shown to the medical room where a registered nurse took physical observations and a baseline blood sample. All subsequent assessments were undertaken under the supervision of a research assistant. Participants completed a baseline PANAS mood scale. Under doubleblind supervision, they then ingested an oral dose of MDMA, methamphetamine, or placebo. For the 3 h following drug administration, each participant engaged in quiet restful activities, with free access to videos, books, magazines, and the internet. Participants were monitored throughout this waiting period. They were allowed cigarettes only in the ‘smoking’ area. Three hours after drug administration, the participant accompanied the nurse to the medical room where a second blood sample was taken. Participants then completed the 3-hour PANAS mood scale. The four driving simulator scenarios were performed, followed by the cognitive tests, and standardized Field Sobriety Tests (SFSTs). Participants then completed a short questionnaire covering perceived drug side effects, a post-driving self-assessment, and the 4.5 h PANAS mood scale. Taxis were provided for transport home. The following morning, they returned to the laboratory by taxi for the 24-h post-drug administration session. There, a final blood sample was taken, the driving simulator task performed again, and the cognitive tests completed. The final 24-h PANAS was also given, along with a questionnaire on perceived drug side effects, and the driving self-assessment.
Statistical analysis Initial one way analyses of variance (ANOVA) were conducted to ensure that there were no baseline differences between treatment conditions. Scores from the positive and negative scales of the PANAS were then analyzed by two-way repeated measures ANOVAs with treatment (placebo, MDMA, methamphetamine) and Time (baseline, 3 h, 4.5 h, 24 h) as the two factors. In the case of significant interactions, Sidak pairwise comparisons were conducted to determine the significance of differences between treatment conditions at each time point. Given the possibility of gender differences, a secondary analysis was conducted using three-way ANOVAs for treatment×time×gender, the last being a between-subjects
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factor, for each PANAS scale. A further series of one-way ANOVA was undertaken within each drug condition, followed by Sidak pairwise comparisons between baseline and each post-drug test session. The statistical analyses were performed using SPSS for Windows v17.
Results The drug usage histories are shown in Table 1. The blood levels of MDMA, 3,4-methylenedioxyamphetamine (MDA), and methamphetamine are summarized in Table 2. The mood state changes are presented in Fig. 1. The initial one-way ANOVA of the baseline mood data showed no significant differences between treatments for either positive or negative PANAS scores (F
